Hypertensive Disorders of Pregnancy and Pre-Pregnancy Hypertension with Subsequent Incident Venous Thromboembolic Events

Hypertensive disorders of pregnancy (HDP) and pre-pregnancy hypertension contribute to maternal morbidity and mortality. We examined the association of HDP and pre-pregnancy hypertension with subsequent venous thromboembolic (VTE) events. The retrospective cohort study included 444,859 women with ≥1 live, singleton birth in South Carolina (2004–2016). Hospital and emergency department visit and death certificate data defined incident VTE, HDP, and pre-pregnancy hypertension. Birth certificate data also defined the exposures. Adjusted Cox proportional hazards methods modeled VTE events risk. Of the cohort, 2.6% of women had pre-pregnancy hypertension, 5.8% had HDP, 2.8% had both pre-pregnancy hypertension and HDP (both conditions), and 88.8% had neither condition. The risk of incident VTE events within one year of delivery was higher in women with HDP (hazard ratio [HR] = 1.62, 95% confidence interval [CI]: 1.15–2.29) and both conditions (HR = 2.32, 95% CI: 1.60–3.35) compared to those with neither condition as was the risk within five years for women with HDP (HR = 1.35, 95% CI: 1.13–1.60) and for women with both conditions (HR = 1.82, 95% CI: 1.50–2.20). One- and five-year risks did not differ in women with pre-pregnancy hypertension compared to women with neither condition. Compared to non-Hispanic White (NHW) women with neither condition, the incident VTE event risk was elevated within five years of delivery for NHW (HR = 1.29, 95% CI: 1.02–1.63; HR = 1.59, 95% CI: 1.16–2.17) and non-Hispanic Black (NHB; HR = 1.51, 95% CI: 1.16–2.96; HR = 2.08, 95% CI: 1.62–2.66) women with HDP and with both conditions, respectively, and for NHB women with pre-pregnancy hypertension (HR = 1.50, 95% CI: 1.09–2.07). VTE event risk was highest in women with HDP, and the event rates were higher in NHB women than in NHW women in the same exposure group.


Introduction
The incidence of venous thromboembolism (VTE) during pregnancy in the United States (U.S.) is low at up to 1.72 per 1000 deliveries [1].During pregnancy, VTE risk is approximately five times higher, and in the 3 months subsequent to delivery is 60 times higher than in non-pregnant women [2].This is of public health importance as VTE represents a leading cause of severe maternal morbidity and mortality [3,4].Furthermore, VTE rates are higher among Black women compared to women of other races [1][2][3].Hypertensive disorders of pregnancy (HDP) including gestational hypertension, preeclampsia and eclampsia are significant complications affecting nearly 10% of pregnancies [5,6].Compared with non-Hispanic White (NHW) women, chronic hypertension and HDP rates are higher in non-Hispanic Black (NHB) women [7][8][9][10].Moreover, the risk of maternal 2 of 17 and fetal/neonatal serious morbidity and mortality from HDP is elevated and varies by race and ethnicity [10][11][12].Post-pregnancy cardiovascular outcomes associated with HDP, including mortality, can occur long term [13][14][15][16].
Although the causes and treatments differ for VTE and arterial cardiovascular disease, the pathophysiology between them is shared to some extent [17][18][19][20][21]. Preeclampsia, a type of HDP, and thrombophilia share pathogenic mechanisms resulting in an increased risk of developing VTE.During pregnancy, the risk of VTE is higher, due to anatomic and physiologic changes including the occurrence of a hypercoagulable state of the blood [22].VTE history is associated with an increased risk of preeclampsia and placenta-mediated pregnancy complications [23].Thus, a biologically plausible mechanism for placenta-mediated complications including preeclampsia [24][25][26][27][28] and VTE may be thrombophilia or thrombosis [29][30][31].While relationships have been reported between preeclampsia and other HDP with VTE during pregnancy or postpartum by international studies [32][33][34][35], U.S. studies and evidence regarding potential differences by race/ethnicity are lacking.Therefore, we aimed to evaluate the association between HDP and pre-pregnancy hypertension with incident VTE events among women within one and five years after delivery and over the entire study period (up to fourteen years).We examined the risk of post-pregnancy incident VTE events and related mortality, as well as racial and ethnic group differences.

Materials and Methods
The data used for this study cannot be shared due to the policies of the South Carolina (SC) Revenue and Fiscal Affairs (RFA) Office Health and Demographics Section, and the SC Department of Health and Environmental Control (DHEC).The policies of these data sources also require that small numbers, less than five, be reported as <5.

Study Design
For this retrospective cohort study, existing statewide administrative billing data for SC hospital discharge records and emergency department (ED) visit encounters from the SC RFA Office were utilized.We also used birth certificate and death certificate data available from SC DHEC.Institutional review board approval was received with the requirement for consent waived.

Study Population
Birth certificate data identified live births in SC hospitals.Information on the mothers' demographics, diagnosis and procedure codes (International Classification of Diseases, Ninth and Tenth Revision, Clinical Modification [ICD-9-CM/ICD-10-CM], Supplementary Materials Table S1), patient dispositions, and lengths of stay were available from hospitalization/ED visit data.Death certificate data included demographics, payers, current/previous pregnancies, and causes of maternal death (primary, underlying, comorbid) information.The majority (97.5%) of birth certificates were successfully linked to maternal hospitalization/ED visit data by the SC RFA, with a unique identifier.

Inclusion and Exclusion Criteria
Our study included women with hospitalization/ED visit data and matching birth certificate data for single, liveborn infants delivered in SC hospitals between 2004 and 2016.Maternal hospitalization/ED visit and mortality data were obtained through 2017, providing one to fourteen years of follow-up.Figure 1 shows the study inclusion and exclusion criteria.We excluded out-of-state mothers who may not seek care regularly in SC and women with prior kidney transplants who may not be representative of the pre-pregnancy hypertension and HDP exposure groups.Because of small numbers and data accuracy concerns, a pre-pregnancy weight of <92 or >320 lbs, a pre-pregnancy BMI of <16.0 or >52.8 kg/m 2 , newborns with birth weights of <500 or >6000 g, and deliveries with implausible size for gestational age were excluded [36].
pregnancy weight of <92 or >320 lbs, a pre-pregnancy BMI of <16.0 or >52.8 kg/m 2 , newborns with birth weights of <500 or >6000 g, and deliveries with implausible size for gestational age were excluded [36].

Definitions
Maternal information available from the birth certificate included self-reported race and ethnicity, education, primary payer, BMI at delivery and pre-pregnancy, smoking during and pre-pregnancy, pre-pregnancy and gestational hypertension, and pre-pregnancy and gestational diabetes mellitus.Self-reported race and ethnicity was categorized as NHW, NHB, Hispanic, or other race and ethnicity.Other race and ethnicity included Asian, American Indian, and women of other races and ethnicities.Prenatal care adequacy and utilization information based on the Revised-Graduated Prenatal Care Utilization Index (R-GINDEX) was available that combined the number of visits with the trimester and gestational age prenatal care began [37,38].The six R-GINDEX categories are inadequate, intermediate, adequate, intensive, no care, or not able to calculate due to missing information, although quality of service is not evaluated.
Hospitalization/ED visit data included ICD-9/10-CM diagnosis and procedure codes used to define the exposure, outcome, and covariates (Table S1).The four exposure groups were women (1) with superimposed preeclampsia termed pre-pregnancy hypertension with superimposed HDP (referred to as "both conditions"), (2) with HDP without pre-

Definitions
Maternal information available from the birth certificate included self-reported race and ethnicity, education, primary payer, BMI at delivery and pre-pregnancy, smoking during and pre-pregnancy, pre-pregnancy and gestational hypertension, and pre-pregnancy and gestational diabetes mellitus.Self-reported race and ethnicity was categorized as NHW, NHB, Hispanic, or other race and ethnicity.Other race and ethnicity included Asian, American Indian, and women of other races and ethnicities.Prenatal care adequacy and utilization information based on the Revised-Graduated Prenatal Care Utilization Index (R-GINDEX) was available that combined the number of visits with the trimester and gestational age prenatal care began [37,38].The six R-GINDEX categories are inadequate, intermediate, adequate, intensive, no care, or not able to calculate due to missing information, although quality of service is not evaluated.
Hospitalization/ED visit data included ICD-9/10-CM diagnosis and procedure codes used to define the exposure, outcome, and covariates (Table S1).The four exposure groups were women (1) with superimposed preeclampsia termed pre-pregnancy hypertension with superimposed HDP (referred to as "both conditions"), (2) with HDP without pre-pregnancy hypertension ("HDP"), (3) with pre-pregnancy hypertension without superimposed HDP ("pre-pregnancy HTN"), and (4) without pre-pregnancy hypertension or HDP ("neither condition").HDP was defined by a birth certificate checkbox for gestational hypertension, which also included preeclampsia and eclampsia, or by hospitalization/ED visit data as gestational hypertension, preeclampsia, or eclampsia (ICD-9/10-CM: 642.3-642.7;O11-O16).Pre-pregnancy hypertension was defined by a birth certificate checkbox or hospitalization/ED visit data (ICD-9/10-CM: 642.0-642.2;O10).Pre-pregnancy hypertension with superimposed HDP was defined by birth certificate data and/or from hospitalization/ED visit data (ICD-9/10-CM: 642.7;O11-O12, O14-O15), with the understanding that this refers to preeclampsia.The first pregnancy in the dataset among women with neither condition and with HDP and/or pre-pregnancy hypertension was considered the index pregnancy.Diagnoses with ICD-9/10-CM codes in the hospitalization/ED visit and death certificate data as shown in Table S1 defined fatal and nonfatal maternal VTE events (VTE, PE, DVT) and arterial embolism or thrombosis.If an individual had multiple VTE events, only the first was counted.Cerebral venous thrombosis was also examined (ICD-9/10-CM codes: 437.6 and I67.6) although less than five events occurred throughout the study period.

Statistical Analysis
We used Chi-square tests to analyze categorical variables and analysis of variance to analyze continuous variables by group differences.Cox proportional hazards models were used to calculate HRs and corresponding 95% CIs to estimate incident VTE events/deaths within one and five years after delivery and over the entire study period (up to fourteen years after delivery).Schoenfeld residuals were used to check the proportional hazards assumption.Models included time from delivery to event or death and were adjusted for significant sociodemographic (maternal age at delivery; race and ethnicity; education; urban/rural residence; median household income per year; payer during pregnancy; Women, Infants, and Children [WIC] eligibility during pregnancy), behavioral (smoking during pregnancy), and clinical characteristics (pre-pregnancy BMI, change in BMI after delivery, pre-pregnancy or gestational diabetes mellitus, gestational age at delivery, mode of delivery [cesarean section (C-section) or vaginal], induced labor, number of pregnancies prior to index pregnancy, previous C-section, previous pre-term delivery, R-GINDEX).The R-GINDEX included a missing category, and previous C-section included an unknown category since this was one of the categories provided on the birth certificate.Sensitivity analyses were performed to examine the hazard of incident VTE events excluding arterial embolism within one and five years after delivery and over the entire study period (up to fourteen years after delivery).
For comparisons by racial and ethnic group, NHW women with neither condition served as the reference group and a joint analysis was carried out as VTE event rates varied at baseline.Hispanic and women of other racial/ethnic groups were included in the overall models but were excluded from race/ethnicity-specific models because of small numbers of incident VTE events especially when examined by exposure group (n = 96 and n = 25 throughout the study period, respectively).In a sensitivity analysis, the hazard of incident VTE events/deaths within one and five years of delivery as well as the entire study period (up to fourteen years after delivery) was examined among women stratified by race/ethnic group.Statistical analyses were performed using SAS Version 9.4 (SAS Institute Inc., Cary, NC, USA) [39].Stata Version 13 was used to create graphs and to check the proportional hazards assumption [40].
Sociodemographic and clinical characteristics are shown by exposure group in Table 1.Women with pre-pregnancy hypertension or both conditions were more likely than those with HDP or neither condition to be older and have a rural residence and a previous C-section.Women with pre-pregnancy hypertension, HDP, or both conditions were more likely to be NHB, WIC eligible during pregnancy, and to have pre-pregnancy or gestational diabetes mellitus, induced labor, Medicaid, a lower annual household income, a C-section, and a higher BMI pre-pregnancy than women with neither condition.They were also more likely to have a lower gestational age at delivery and to have received intensive or adequate (women with pre-pregnancy hypertension and HDP) prenatal care, as measured using the R-GINDEX than women with neither condition.

Incident VTE Events Subsequent to HDP and/or Pre-Pregnancy Hypertension
Table 2 displays the adjusted hazard of incident VTE events within one, five, and fourteen years of delivery by exposure status compared to women with neither condition.Within fourteen years of delivery, 3762 VTE events (n = 2356 PE, n = 1245 venous embolism, n = 121 arterial embolism) occurred; this also includes less than five cerebral venous thrombosis events and events not specified.Risk of VTE events within one year of delivery increased 62% (95% CI: 1.15-2.29)among women with HDP and 2.32-fold among women with both conditions (95% CI: 1.60-3.35)compared to women with neither condition.Risk of VTE events within five years of delivery was also elevated among women with HDP (HR = 1.35, 95% CI: 1.13-1.60)and both conditions (HR = 1.82, 95% CI: 1.50-2.20).Over the entire study period of up to fourteen years after delivery, risk of VTE events was increased for women with pre-pregnancy hypertension (HR = 1.36, 95% CI: 1.18-1.58),HDP (HR = 1.31, 95% CI: 1.16-1.48),and both conditions (HR = 1.74, 95% CI: 1.52-2.00)compared to women with neither condition.
A sensitivity analysis was performed in which the VTE definition was limited to venous VTE events (excluding arterial embolism).The adjusted hazards within one, five, and fourteen years of delivery by exposure status compared to women with neither condition are given in Table S2, Supplementary Materials; the results were not significantly different from those above.Pre-pregnancy hypertension with superimposed HDP was based on hospitalization/ED visit data (ICD-9/10-CM: 642.7;O11-O12, O14-O15) or a combination of the above diagnosis codes for HDP and pre-pregnancy hypertension. 2Smoking during pregnancy, pre-pregnancy BMI, BMI at delivery, gestational age at delivery, mode of delivery, induced labor, number of pregnancies prior to the index pregnancy, previous cesarean section, pre-pregnancy diabetes, and gestational diabetes were available from the birth certificate.Gestational diabetes mellitus was also defined using hospitalization/ED visit data based on ICD-9/10-CM codes. 3Variables with >0.1% missing data included annual household income, n = 9297; prenatal care as measured via R-GINDEX, n = 126,955; primary payer, n = 3339; and WIC eligibility in pregnancy, n = 7070.

Racial and Ethnic Differences in Incident VTE Events Following HDP and/or Pre-Pregnancy Hypertension
Racial and ethnic differences in incident VTE event rates and risk within five years of delivery are displayed in Table 3 for NHW and NHB women only, owing to a small number of events among Hispanic women and women of other race/ethnic groups.In general, NHB women had higher incident VTE event rates than their NHW counterparts regardless of the exposure.The number of incident VTE events was small in women with pre-pregnancy hypertension.The VTE event rate (per 1000 person-years) within one year in women with pre-pregnancy hypertension was 0.97 in NHW women and 0.51 in NHB women; within five years, the rates were 0.89 and 1.48, respectively; and incident VTE rates for the full period of follow-up were 1.48 in NHW women and 2.33 in NHB women.
The VTE event rate (per 1000 person-years) within one, five, and fourteen years in women with HDP was higher in NHB women (1.99, 1.55, and 2.11) than in NHW women (1.46, 1.08, and 1.33), respectively.Similarly, the VTE event rate (per 1000 person-years) within one, five and fourteen years in women with both conditions was higher in NHB women (4.29, 2.75, and 3.07) than in NHW women (2.14, 1.58, and 2.12), respectively.Figure 2 presents race-specific incident VTE event rates per 1000 person-years (95% CI) for NHW women and NWB women within five years of delivery.
The adjusted hazard of maternal incident VTE events was compared among NHW and NHB women in a joint analysis with NHW women with neither condition serving as the reference group (Table 3).NHB women with both conditions experienced an increased risk of incident VTE events within one (HR = 2.90, 95% CI: 1.80-4.66)and five years of delivery (HR = 2.08, 95% CI: 1.62-2.66)as well as over the entire study period (up to fourteen years after delivery; HR = 2.13, 95% CI: 1.78-2.55)compared to NHW women with neither condition.Compared to NHW women with neither condition, NHW women with both conditions had an increased risk of incident VTE events within one (HR = 2.01, 95% CI: 1.10-3.68)and five (HR = 1.59, 95% CI: 1.16-2.17)years of delivery and over the entire study period (HR = 1.79, 95% CI: 1.43-2.23).
Women with pre-pregnancy hypertension had a small number of incident VTE events.NHW women with pre-pregnancy hypertension did not differ from NHW women with neither condition within one or five years after delivery but did have a significantly increased risk of VTE over the entire study period (HR = 1.32, 95% CI: 1.03-1.69).NHB women with pre-pregnancy hypertension did not differ from NHW women with neither condition within one year of delivery but did show a significantly increased risk of VTE within five years after delivery (HR = 1.50, 95% CI: 1.09-2.07)and over the entire study period (HR = 1.78, 95% CI: 1.48-2.15).
Compared to NHW women with neither condition, NHB women with neither condition had an increased risk of incident VTE events over the entire study period (HR = 1.27, 95% CI: 1.17-1.38).An interaction between the exposure and racial and ethnic groups with incident VTE events was tested for but not significant (p = 0.72 within one, p = 0.46 within five, and p = 0.95 within fourteen years of delivery [study period]).Table S3, Supplementary Materials, presents event rates and the adjusted hazard of incident VTE events within one and five years of delivery and the entire study period (up to fourteen years after delivery) among women stratified by race/ethnic group.In general, the HRs were similar to those of the racial/ethnic-specific joint models or attenuated, remaining significant except for NHB women with HDP compared to NHB women with neither condition.However, the results of these models must be interpreted with caution, as the baseline rates of VTE events differ in NHB and NHW women.
Table 3.The adjusted hazard of fatal and nonfatal incident venous thromboembolic (VTE) events within one and five years of delivery as well as the entire study period (up to fourteen years after delivery) among women by race/ethnic group.

Discussion
In a statewide retrospective cohort study in SC, we evaluated the relationship between HDP and pre-pregnancy hypertension with short-term (within one year) and longterm (within five years and throughout the study period of up to fourteen years after delivery) maternal post-pregnancy VTE events.Increased risk of incident VTE events was observed for women with HDP and/or pre-pregnancy hypertension with event rates highest for NHB women.Compared with NHW women, NHB women experienced higher risk of incident VTE events.
Our overall findings are consistent with those of recent studies.A Dutch nationwide cohort study (n = 1,919,918; 24,531,118 person-years) reported the adjusted risk of VTE during pregnancy and ≤3 months after delivery was doubled in women with hypertension during pregnancy compared to those with pregnancy complications and was nearly 8fold higher among women with preeclampsia than women without pregnancy complications [35].Over the follow-up period (≤13 years after first delivery), women with hypertension during pregnancy (1.5-fold) and preeclampsia (2.1-fold) were at increased VTE risk after adjustment [35].Moreover, the risk attenuated slightly although it remained significant over the follow-up period after limiting VTE events to >3 months postpartum [35].The aforementioned study did not consider pre-pregnancy hypertension or involve deaths.We were interested in including women exposed to HDP as well as pre-pregnancy hypertension to evaluate fatal and non-fatal incident VTE events across four exposure groups compared to women with neither condition.Thus, our findings provide an important contribution to the literature and evidence from a U.S. study as many studies have been international.
Most recently, in a nationwide cohort study in Denmark with 10.2 years median follow-up, a 43% elevated risk of VTE was observed among primiparous women with and without preeclampsia following adjustment [31].A 2020 review by Hart et al. reported a number of pregnancy-related factors that have been associated with VTE including preeclampsia (3-fold increase) [22].The odds of VTE were 1.5 times higher among women with prior HDP than without prior HDP after adjustment for age at enrollment and race

Discussion
In a statewide retrospective cohort study in SC, we evaluated the relationship between HDP and pre-pregnancy hypertension with short-term (within one year) and long-term (within five years and throughout the study period of up to fourteen years after delivery) maternal post-pregnancy VTE events.Increased risk of incident VTE events was observed for women with HDP and/or pre-pregnancy hypertension with event rates highest for NHB women.Compared with NHW women, NHB women experienced higher risk of incident VTE events.
Our overall findings are consistent with those of recent studies.A Dutch nationwide cohort study (n = 1,919,918; 24,531,118 person-years) reported the adjusted risk of VTE during pregnancy and ≤3 months after delivery was doubled in women with hypertension during pregnancy compared to those with pregnancy complications and was nearly 8-fold higher among women with preeclampsia than women without pregnancy complications [35].Over the follow-up period (≤13 years after first delivery), women with hypertension during pregnancy (1.5-fold) and preeclampsia (2.1-fold) were at increased VTE risk after adjustment [35].Moreover, the risk attenuated slightly although it remained significant over the follow-up period after limiting VTE events to >3 months postpartum [35].The aforementioned study did not consider pre-pregnancy hypertension or involve deaths.We were interested in including women exposed to HDP as well as pre-pregnancy hypertension to evaluate fatal and non-fatal incident VTE events across four exposure groups compared to women with neither condition.Thus, our findings provide an important contribution to the literature and evidence from a U.S. study as many studies have been international.
Most recently, in a nationwide cohort study in Denmark with 10.2 years median follow-up, a 43% elevated risk of VTE was observed among primiparous women with and without preeclampsia following adjustment [31].A 2020 review by Hart et al. reported a number of pregnancy-related factors that have been associated with VTE including preeclampsia (3-fold increase) [22].The odds of VTE were 1.5 times higher among women with prior HDP than without prior HDP after adjustment for age at enrollment and race in the prospective, observational United Kingdom Biobank study [41].Studies conducted in Norway (registry-based case-control) and Canada (retrospective cohort) found women with preeclampsia compared to those without preeclampsia had a 3.8-fold increase in odds [32] and a 2.2-fold higher risk [33] of post-pregnancy VTE after covariate adjustment, respectively.Women with eclampsia experienced a 4.4-fold increase in the odds of postpregnancy VTE than those without eclampsia after adjustment in the Norwegian study [32].Increased postpartum VTE event risk was similarly reported to be tripled among women with preeclampsia after adjustment by a Swedish retrospective population-based study [34].Using the U.S. Healthcare Cost and Utilization Project National Readmissions Database, of the more than 6 million delivery hospitalizations between 2013 and 2014, VTE readmissions within 60 days of discharge were estimated as being 4.7/10,000 [42].Preeclampsia and gestational hypertension diagnoses were present among 8.2% and 19.7% of women with VTE readmissions, respectively (p < 0.01) [42].Women with preeclampsia or gestational hypertension had twice the odds of being readmitted for VTE [42].Potential race or ethnic differences could not be examined as this information was not available.However, not all studies have found a relationship.The U.S. National Inpatient Sample (2000)(2001) did not observe an independent association between preeclampsia and gestational hypertension with VTE (OR = 0.9, 95% CI: 0.7-1.0),although certain medical conditions including hypertension increased the risk of pregnancy-related VTE 1.8-fold [43].
We had the advantage of being able to compare racial/ethnic differences among NHW and NHB women, whereas other studies were limited in their ability to assess potential racial or ethnic differences due to homogeneous populations [32][33][34] with only one study assessing descent (Dutch, Hindustani, other) in VTE risk among women with hypertension during pregnancy [35].NHB women are a critical group to study because of their high risk of cardiovascular disease risk factors as well as HDP and related outcomes in general [44,45].In a U.S. statewide case-control study, the odds of VTE at delivery or during the three months postpartum were 1.5-fold higher for Black women and 0.67-fold lower for Asian women than NHW women after covariate adjustment including preeclampsia [46].Among White and Black women with adverse pregnancy outcomes, any thrombophilia was found to be more common among White women due primarily to Factor V Leiden mutation, whereas Black women were more likely to be diagnosed with protein S or antithrombin deficiencies [47].A history of pregnancy loss(es), preeclampsia, preterm delivery, placental abruption, and intrauterine growth restriction defined adverse pregnancy outcomes with pregnancy losses making up about 90% [47].Sickle cell disease or other comorbidities, resistance to fibrinolysis, and higher coagulation-factor levels (e.g., fibrinogen) are possible reasons that Black women are more likely to experience pregnancy-associated VTE [48,49].However, the evidence is lacking, and a gap currently exists in the literature regarding differences that may exist by race/ethnicity in the relationship between HDP and VTE.Our study is the first to our knowledge to compare the risk of VTE following HDP by race/ethnicity.The public health implications of the findings from the current study as well as future investigations include the possibility of improved screening and monitoring of women of racial/ethnic minority groups and other subgroups found to be at high risk of adverse pregnancy-related outcomes.Additional research could be conducted to identify factors associated with health disparities in the relationship between HDP and VTE.This, in turn, could contribute to a reduction in poor pregnancy-associated outcomes for women with pre-existing risk factors including comorbidities, especially those at high risk.
VTE risk is higher in pregnancy, during which anatomic and physiologic changes are present including the occurrence of a hypercoagulable state of blood [22].Physiologic anticoagulants are decreased, whereas some coagulation factors are increased in pregnancy.Preeclampsia begins with abnormal placentation followed by induced endothelial damage [50] that can possibly also result from delivery-related trauma.As the uterus expands, the inferior vena cava and pelvic veins in the lower extremities are compressed, and venous dilatation can result from progesterone levels [22].Because the clinical characteristics are continuously changing, VTE is a dynamic condition [51] that can be due to hereditary and/or acquired causes.Hypercoagulability is also a cause of VTE in addition to damage to the vascular tissue and abnormal hemodynamics [52].Hereditary risk factors for VTE include Factor V Leiden, Prothrombin G20210A, and deficiency in protein S, protein C, or antithrombin, whereas some therapies and many disorders (e.g., heart failure, obesity, pregnancy) are acquired risk factors [53].High venous resistance, elevated coagulability and inflammation, as well as endothelial lining damage are related to higher VTE risk [52].History of VTE has been reported to increase the risk of preeclampsia 50% as well as other placenta-mediated pregnancy complications [23].A biologically plausible mechanism for placenta-mediated complications including preeclampsia [24][25][26][27][28] and VTE could be thrombophilia or thrombosis [29][30][31].
Women with a history of VTE events are treated with anticoagulation during pregnancy and postpartum.Anticoagulation is also used under other clinical circumstances including after C-section in patients with risk factors for VTE events such as obesity, admission with COVID-19-related complications, and prolonged hospitalization.For instance, all patients admitted to the antepartum unit for ≥72 h receive prophylactic anticoagulation.Although these preventive measures result in short-term VTE risk reduction, our findings are consistent with others that demonstrate the continued association of HDP with VTE events remote from delivery, independent of pre-pregnancy hypertension in the maternal venous system.It is also possible a shared biological risk factor increases the risk of both HDP and VTE [31].

Strengths and Limitations
Our statewide population-based study included thirteen years of data on live, singleton births with up to fourteen years of follow-up available.Approximately 32% of the cohort included understudied NHB women, a group that experiences increased maternal morbidity and mortality.The administrative data sources used for this study provided a wealth of information.Prenatal care, delivery diagnoses (e.g., preterm delivery), information from previous births (e.g., C-section), self-reported race and ethnicity, parity, and other covariates (e.g., pre-pregnancy BMI and smoking) were available from birth certificate data.The R-GINDEX provided prenatal care information for approximately 72% of women with available data.
There are some limitations of this work.Our data sources may have underestimated the number of women in relation to the exposure given inconsistencies in the accuracy of preeclampsia and pre-pregnancy hypertension diagnosis codes [54].To minimize the risk of information bias, all available data sources were used which included inpatient hospitalization discharge records, ED visit records, and birth certificates.Birth certificate and maternal hospitalization/ED visit data were able to be successfully linked for nearly all the cohort (97.5%).Using only hospitalization/ED visit and death certificate data, as we did not have access to outpatient data on incident VTE events, may have underestimated the outcome.Our data sources did not include information on onset, duration, severity, or HDP type such as preeclampsia, although models controlled for a proxy of HDP severity (continuous gestational age at delivery).Without access to medical records prior to delivery, our study was limited to pre-pregnancy hypertension as reported on the birth certificate which may result in underestimation.We also did not have information on previous history of VTE or clotting disorders or current use of blood thinners and thus were not able to exclude individuals with these conditions.There were a small number of events among women with pre-pregnancy hypertension resulting in low power.Few events were observed among Hispanic women and women of other races/ethnicities; therefore, racial and ethnic group differences could not be examined for these groups.Except for women who experienced hospitalization, an ED visit, or an event, we presumed loss to follow-up did not occur.While some women could have moved away from SC, our data sources could not determine this.Finally, we acknowledge the limitations of our retrospective observational study design which provides a weaker level of evidence compared to randomized and prospective studies.

Conclusions
In a retrospective cohort study, we investigated the association of HDP and prepregnancy hypertension with post-pregnancy VTE events up to one and five years after delivery as well as over the entire study period (within 14 years of delivery) in a diverse group of women who had one or more live, singleton births in SC.This study had the ability to compare differences by racial/ethnic group and to include a large number of cases and a long duration of follow-up, allowing examination of the outcome at multiple points.Our study reported an increased risk of VTE events among women with HDP regardless of the presence of pre-pregnancy hypertension.Compared with NHW women, NHB women in every exposure group and time period experienced higher rates of VTE events, except for pre-pregnancy hypertension within one year of delivery.

Supplementary Materials:
The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/ijerph21010089/s1,Table S1: International Classification of Diseases, Ninth and Tenth Revision, Clinical Modification (ICD-9/10-CM) codes for hospitalization and emergency department visit encounters or as reported on birth or death certificates to define the outcome, exposure, and covariates of interest.Table S2.The hazard of fatal and nonfatal incident venous thromboembolic (VTE) events excluding arterial embolism among women by exposure group within one and five years of delivery as well as the entire study period (up to fourteen years after delivery).Table S3.The adjusted hazard of fatal and nonfatal incident venous thromboembolic (VTE) events within one and five years of delivery as well as the entire study period (up to fourteen years after delivery) among women stratified by race/ethnic group.

Figure 1 .
Figure 1.Study inclusion and exclusion criteria flowchart.

Figure 1 .
Figure 1.Study inclusion and exclusion criteria flowchart.

Figure 2 .
Figure 2. Maternal incident venous thromboembolic (VTE) events (per 1000 person-years) up to five years after delivery by exposure and racial and ethnic group.HDP, hypertensive disorders of pregnancy.

Figure 2 .
Figure 2. Maternal incident venous thromboembolic (VTE) events (per 1000 person-years) up to five years after delivery by exposure and racial and ethnic group.HDP, hypertensive disorders of pregnancy.

Table 1 .
Index pregnancy characteristics of mothers who gave birth in South Carolina between 2004 and 2016 1,2,3 .

Table 2 .
The adjusted hazard of fatal and nonfatal incident venous thromboembolic (VTE) events among women by exposure group within one and five years of delivery as well as the entire study period (up to fourteen years after delivery).
CI, confidence interval; HDP, hypertensive disorders of pregnancy; HR, hazard ratio; HTN, hypertension.1Per1000person-years. 2justed for sociodemographic characteristics (maternal age; race/ethnicity; education; rural/urban residence; annual household income; primary payer during pregnancy; Women, Infants and Children [WIC] eligibility during pregnancy), a behavioral characteristic (smoking during pregnancy), and clinical characteristics (pre-pregnancy body mass index [BMI], number of pregnancies after index pregnancy, gestational age at delivery, mode of delivery, induced labor, previous cesarean section [C-section], previous pre-term delivery, Revised Graduated Prenatal Care Utilization Index [R-GINDEX], and pre-pregnancy or gestational diabetes).3Bolddenotes statistical significance.